PHILADELPHIA — Total anomalous pulmonary venous connection (TAPVC), one type of “blue baby” syndrome, is a potentially deadly congenital disorder that occurs when pulmonary veins don’t connect normally to the left atrium of the heart. This results in poorly oxygenated blood throughout the body, and TAPVC babies are born cyanotic — blue-colored — from lack of oxygen.

TAPVC is usually detected in newborns when babies are blue despite breathing normally. Life-threatening forms of the disorder are rare – about 1 in 15,000 live births. A closely related, but milder disorder, partial anomalous pulmonary venous connection (PAPVC), in which only some of the pulmonary veins go awry, is found in as many as 1 in 150 individuals.

Now, researchers have found that a mutation in a key molecule active during embryonic development makes the plumbing between the immature heart and lungs short-circuit, disrupting the delivery of oxygenated blood to the brain and other organs. The mutation ultimately causes blood to flow in circles from the lungs to the heart’s right side and back to the lungs.

Senior author Jonathan A. Epstein, MD, chair of the Department of Cell and Developmental Biology, at the Perelman School of Medicine, University of Pennsylvania, and colleagues from The Children’s Hospital of Philadelphia, describe in Nature Medicine, that a molecule called Semaphorin 3d (Sema3d) guides the development of endothelial cells and is crucial for normal development of pulmonary veins. It is mutations in Sema3d that cause embryonic blood vessels to hook up in the wrong way.

Epstein is also the William Wikoff Smith professor and scientific director of the Penn Cardiovascular Institute. Karl Degenhardt, MD, PhD, assistant professor at The Children’s Hospital of Philadelphia; Manvendra K. Singh, PhD, an instructor of Cell and Developmental Biology at Penn; and Haig Aghajanian, a graduate student in Cell and Molecular Biology at Penn are the co-first authors on the paper.

Physicians thought that TAPVC occurred when the precursor cells of the pulmonary vein failed to form at the proper location on the embryonic heart atrium. However, analysis of Sema3d mutant embryos showed that TAPVC occurs despite normal formation of embryonic precursor veins.

An example of a mouse with TAPVC as seen by microCT. The movie starts off looking from the left side. As the specimen spins you can see the pulmonary veins (PV) connecting to the coronary sinus (CS) from the back. LSVC = left superior vena cava, RSVC = right superior vena cava, LA = left atrium, RA = right atrium, LV = left ventricle.

Scans through developing mouse hearts. The arrow points to a pulmonary vein that goes from the lung to the left atrium in a normal mouse (left). In the mutant (right), follow the pulmonary vein (arrow) from the lung to the coronary sinus (CS), which connects to the right atrium.

A cell that makes Sema3d repels the endothelial cells (left). Endothelial cells are not repelled by a control cell making green fluorescent protein (GFP, right). The endothelial cells will touch the GFP cell and not move away. Mutant cells that do not make Sema3d would behave like the ‘GFP’ cell – unable to repel endothelial cells and therefore unable to prevent abnormal vessel formation.

Credit: Perelman School of Medicine, University of Pennsylvania; The Children’s Hospital of Philadelphia: Nature Medicine

In these embryos, the maturing pulmonary venous plexus, a tangle of vessels, does not connect just with properly formed precursor veins. In the absence of the Sema3d guiding signal, endothelial tubes form in a region that is not normally full of vessels, resulting in aberrant connections. Normally, Sema3d provides a repulsive cue to endothelial cells in this area, establishing a boundary.

Sequencing of Sema3d in individuals affected with anomalous pulmonary veins identified a point mutation that adversely affects Sema3d function in humans. The mutation causes Sema3d to lose its normal ability to repel certain types of cells to be able to guide other cells to grow in the correct place. When Sema3d can’t keep developing veins in their proper space, the plumbing goes haywire.

Since it’s already known that semaphorins guide blood vessels and axons to grow properly, the authors surmise that Sema3d could be used for anti-angiogenesis therapies for cancer, to treat diabetic retinopathy, or to help to grow new blood vessels to repair damaged hearts or other organs.

This work was supported by the National Institutes of Health (NIH 5K12HD043245-07, NIH T32 GM07229, and NIH UO1 HL100405).

T-helper cells that are present in peripheral tissues are known to be a prominent source of IL17. These cells interact with microbial organisms, in particular in the gastrointestinal tract, and are instructed or “induced” to produce and secrete IL17. These inducible, T-helper, IL17-producing cells are found predominantly at mucosal sites and are important for maintaining the health of these tissues.

“Natural” IL17-producing cells, on the other hand, do not have to interact with microorganisms to become capable of making this important cytokine. What these natural IL17-producing T cells do and how they are instructed to produce IL17 has become a research focus for Jordan and Koretzky.

“Although we know much less about natural IL17-producing cells, previous work from our laboratory demonstrated that these cells obtain their ability to produce this cytokine as they develop in the thymus,” says Koretzky. “The current study in NatureImmunology compares the signals used by inducible versus natural IL-17 cells that are necessary for cytokine production, testing the hypothesis that they are distinct populations of cells. This may one day help us to develop tools to manipulate one cell population while leaving the other untouched.”

The team found evidence that the inducible versus natural cells do, in fact, have very different characteristics. Although the kinase Akt plays a critical role in regulating cytokine production by both cell types, how these cell types use Akt differs. For example, mTORC1, a protein complex activated by Akt, is critical for the generation of inducible IL17-producing cells in the gut; however, natural IL17 cells develop independently of mTORC1. This finding suggests that the trigger for the development of inducible versus natural IL17-producing cells is different. To probe this finding further, Koretzky and Jordan focused attention on different forms of Akt.

Previous work by many laboratories defined different subtypes of Akt, and emerging data suggest that these forms may have differential functions in various tissues.

This finding was extended to inducible and natural IL17-producing T cells in the current Nature Immunology publication, as the team found that one particular form of Akt — Akt2 — is necessary for optimal inducible cell development but dispensable for natural IL17-producing cells. The findings show how a previously unknown role of Akt and its partner molecules shapes the maturation of IL17-producing cells.

Understanding the rules that govern IL17 cell development and function will suggest ways to specifically modulate one population or the other, which may be important during IL17-mediated immune responses, especially when that response spins out of control.

This work was supported by grants from the National Institutes of Health (R01 DK56886, 5K01AR52802, R37GM053256) and the Abramson Family Cancer Research Institute.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report‘s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.

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